PROJECT SUMMARY/ABSTRACT Transgender women (TGW) are at high risk for HIV infection, and are an important, under-researched population in sub-Saharan Africa. Globally, HIV acquisition risk among TGW is 13 times higher than other adults aged 15- 49 years. In Uganda, HIV prevalence among TGW is 22% compared to 5.9% in the general population. Encouraging use of self-controlled HIV prevention tools ? specifically, HIV self-testing (HIVST), STI self-sampling (STISS) and antiretroviral pre-exposure prophylaxis (PrEP) - to those testing HIV negative could decrease HIV incidence among African TGW. This R34 application proposes formative research and a pilot trial to develop an HIV prevention intervention for African transgender women (TGW). We will evaluate whether peer-delivered combination HIV prevention increases testing uptake and empowers effective prevention decision making in TGW. Peer-led interventions are effective in increasing HIV and STI testing among other hard-to-reach vulnerable populations with high HIV prevalence but low testing coverage, and are recommended by the World Health Organization. Exploring peer-delivery approaches to increase coverage of combination HIV prevention interventions is key to addressing research gaps in HIV epidemic control. However, little is known about the effectiveness of peer-delivered combination HIV prevention (HIVST, STISS and PrEP) for African TGW, or the best way to deliver care to this population. Key knowledge gaps include: 1) whether peer delivery increases testing rates and status knowledge, 2) the role of peers in creating demand for repeat testing and PrEP, and 3) how to optimize peer delivery of combination HIV prevention (HIVST, STISS and PrEP). To address these questions, this proposal seeks to conduct formative research to inform implementation of peer-delivered combination HIV prevention for African TGW (Aim 1), implement a pilot cluster randomized trial to evaluate the feasibility, acceptability and preliminary effectiveness of peer delivered combination HIV prevention (Aim 2), and conduct in-depth interviews to explore how peer-delivery of HIVST, STISS and PrEP influences prevention choices among TGW and sexual partners (Aim 3). This will be the first clinical trial, to our knowledge, to evaluate HIV self-testing and STI self-sampling in HIV-uninfected TGW. Pilot data from TGW and their partners will provide unique perspectives to inform HIV prevention delivery. The proposed proof-of-concept evaluation is uniquely positioned to improve prevention uptake for African TGW - a high-risk, marginalized, and underserved population. Rigorous application of mixed methodologies will generate actionable data for policy and programs, and provide a strong foundation for scalable implementation of cutting edge combination HIV prevention interventions for African TGW. The local transgender community is involved in study design, planning and implementation. This project is supported by the Ugandan Ministry of Health.